Project Summary/Abstract: Development of Teixobactin Analogues Antibiotic-resistant bacteria cause more than 2 million illnesses and more than 23,000 deaths in the US each year, with direct overall societal costs of about $20 billion and additional indirect societal costs of about $35 billion due to lost productivity. Although there is a desperate need for new antibiotics to fight the growing threat of antibiotic-resistant bacteria, the development of new antibiotics has dropped substantially. If effective new antibiotics are not developed, many more people will be sickened and die, at great human and financial cost. The antibiotic teixobactin has generated considerable excitement since its initial report in 2015, because it kills Gram-positive bacteria without detectable resistance and is effective against bacteria that are resistant to other antibiotics. Pathogens against which teixobactin is active include Staphylococcus aureus, Streptococcus pneumoniae and other Streptococci, Bacillus anthracis, and Mycobacterium tuberculosis -- the pathogens that cause staph infections, bacterial pneumonia, anthrax, and tuberculosis. Teixobactin is effective against bacteria that have developed resistance to other antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Teixobactin is also effective against Clostridium difficile, which has become a particular problem as a result of other antibiotics. Although antibiotics are often discovered as natural products, many of the clinically useful antibiotics are homologues that have been developed to enhance pharmacological properties. The promise of teixobactin is limited by the propensity of this natural product to form insoluble gels upon dissolution in serum or buffer. This proposal seeks to develop analogues of teixobactin with enhanced pharmacological properties and to better understand the relationship between the gelation of teixobactin and its antibiotic activity. The proposal will achieve these goals by synthesizing and studying a series of teixobactin analogues, first in vitro and then in mice. The outcome of the proposal will be an enhanced understanding of the teixobactin pharmacophore and potent teixobactin analogues with good pharmacological properties that are promising preclinical candidates. The broad, long-term objective is to develop new antibiotics that translate to the clinic and save lives of patients with life-threatening infections. These goals will be achieved by designing, synthesizing, and studying of a set of increasingly diverse teixobactin analogues. The first analogues that will be explored involve simple perturbations in the teixobactin structure, through positional SAR studies, N-methylation, and the creation of peptoid analogues. Dimeric, lipidated, and ring-expanded analogues will then be expored. Successful design features will be mixed and matched to further create promising preclinical candidates.